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These results were confirmed in vivo in a patient-derived xenograft model. Collectively, our results nominate cystine import as a druggable target in AML and raise the possibility to repurpose sulfasalazine for the treatment of AML, notably in combination with chemotherapy.Radioimmunotherapy (RIT) has long been pursued to improve outcomes in acute leukemia and higher-risk myelodysplastic syndrome (MDS). Of increasing interest are alpha-particle-emitting radionuclides such as astatine-211 (211At) as they deliver large amounts of radiation over just a few cell diameters, enabling efficient and selective target cell kill. Here, we developed 211At-based RIT targeting CD123, an antigen widely displayed on acute leukemia and MDS cells including underlying neoplastic stem cells. We generated and characterized new murine monoclonal antibodies (mAbs) specific for human CD123 and selected four, all of which were internalized by CD123+ target cells, for further characterization. All mAbs could be conjugated to a boron cage, isothiocyanatophenethyl-ureido-closo-decaborate(2-) (B10), and labeled with 211At. CD123+ cell targeting studies in immunodeficient mice demonstrated specific uptake of 211At-labeled anti-CD123 mAbs in human CD123+ MOLM-13 cell tumors in the flank. In mice injected intravenously with MOLM-13 cells or a CD123NULL MOLM-13 subline, a single dose of up to 40 µCi of 211At delivered via anti-CD123 mAb decreased tumor burdens and substantially prolonged survival dose dependently in mice bearing CD123+ but not CD123- leukemia xenografts, demonstrating potent and target-specific in vivo anti-leukemia efficacy. These data support the further development of 211At-CD123 RIT toward clinical application.To determine whether antigen presentation by HLA-DR on hematopoietic stem progenitor cells (HSPCs) is involved in the development of acquired aplastic anemia (AA), we studied the HLA-DR expression on CD45dimCD34+CD38+ cells in the peripheral blood of 61 AA patients including 23 patients possessing HLA-class I allele-lacking (HLA-class I[-]) leukocytes. HLA-DR-lacking (DR[-]) cells accounted for 13.0-57.1% of the total HSPCs in seven (11.5%) patients with HLA-DR15 who did not possess HLA-class I(-) leukocytes. The incubation of sorted DR(-) HSPCs in the presence of IFN-γ for 72 h resulted in the full restoration of the DR expression. selleck inhibitor A comparison of the transcriptome profile between DR(-) and DR(+) HSPCs revealed the lower expression of immune response-related genes including co-stimulatory molecules (e.g., CD48, CD74, and CD86) in DR(-) cells, which was not evident in HLA-class I(-) HSPCs. DR(-) cells were exclusively detected in GPI(+) HSPCs in four patients whose HSPCs could be analyzed separately for GPI(+) and GPI(-) HSPCs. These findings suggest that CD4+ T cells specific to antigens presented by HLA-DR15 on HSPCs may contribute to the development of AA as well as the immune escape of GPI(-) HSPCs in a distinct way from CD8+ T cells recognizing HLA-class I-restricted antigens.The primary goal of this article is to propose a new fractional boundary element technique for solving nonlinear three-temperature (3 T) thermoelectric problems. Analytical solution of the current problem is extremely difficult to obtain. To overcome this difficulty, a new numerical technique must be developed to solve such problem. As a result, we propose a novel fractional boundary element method (BEM) to solve the governing equations of our considered problem. Because of the advantages of the BEM solution, such as the ability to treat problems with complicated geometries that were difficult to solve using previous numerical methods, and the fact that the internal domain does not need to be discretized. As a result, the BEM can be used in a wide variety of thermoelectric applications. The numerical results show the effects of the magnetic field and the graded parameter on thermal stresses. The numerical results also validate the validity and accuracy of the proposed technique.Complete ammonia oxidizer (Comammox) can complete the whole nitrification process independently, whose niche differentiation is important guarantee for its survival and ecological function. This study investigated the niche differentiation of comammox Nitrospira in the sediments of three typical tributaries of the Three Gorges Reservoir (TGR). Clade A and clade B of comammox Nitrospira coexisted in all sampling sites simultaneously. The amoA gene abundance of clade A and B was gradually increased or decreased along the flow path of the three tributaries with obvious spatial differentiation. The amoA gene abundance of comammox Nitrospira clade A (6.36 × 103 - 5.06 × 104 copies g-1 dry sediment) was higher than that of clade B (6.26 × 102 - 6.27 × 103 copies g-1 dry sediment), and the clade A amoA gene abundance was one order of magnitude higher than that of AOA (7.24 × 102 - 6.89 × 103 copies g-1 dry sediment) and AOB (1.44 × 102 - 1.46 × 103 copies g-1 dry sediment). A significant positive correlation was observed between comammox Nitrospira clade A amoA gene abundance and flow distance (P  less then  0.05). The number of operational taxonomic units (OTUs) in two sub-clades of clade A accounted for the majority in different tributaries, indicating that clade A also had population differentiation among different tributaries. This study revealed that comammox Nitrospira in the sediments of TGR tributaries have niche differentiation and clade A.2 played a more crucial role in comammox Nitrospira community.The sonic excitation of the liquid droplet on a hydrophobic mesh surface gives rise to a different oscillation behavior than that of the flat hydrophobic surface having the same contact angle. To assess the droplet oscillatory behavior over the hydrophobic mesh, the droplet motion is examined under the external sonic excitations for various mesh screen aperture ratios. An experiment is carried out and the droplet motion is recorded by a high-speed facility. The findings revealed that increasing sonic excitation frequencies enhance the droplet maximum displacement in vertical and horizontal planes; however, the vertical displacements remain larger than those of the horizontal displacements. The resonance frequency measured agrees well with the predictions and the excitation frequency at 105 Hz results in a droplet oscillation mode (n) of 4. The maximum displacement of the droplet surface remains larger for the flat hydrophobic surface than that of the mesh surface with the same contact angle. In addition, the damping factor is considerably influenced by the sonic excitation frequencies; hence, increasing sonic frequency enhances the damping factor, which becomes more apparent for the large mesh screen aperture ratios. The small-amplitude surface tension waves create ripples on the droplet surface.Adult-onset Still's disease (AOSD)-a systemic inflammatory disease-often occurs at a young age. Recently, elderly onset patient proportion has been increasing; however, data are limited. To evaluate the characteristics of elderly patients with AOSD in a multicenter cohort, we retrospectively analyzed 62 patients with AOSD at five hospitals during April 2008-December 2020. Patients were divided into two groups according to age at disease onset younger-onset (≤ 64 years) and elderly onset (≥ 65 years). Clinical symptoms, complications, laboratory findings, treatment, and outcomes were compared. Twenty-six (41.9%) patients developed AOSD at age ≥ 65 years. The elderly onset group had a lower frequency of sore throat (53.8% vs. 86.1%), higher frequency of pleuritis (46.2% vs. 16.7%), and higher complication rates of disseminated intravascular coagulation (30.8% vs. 8.3%) and macrophage activation syndrome (19.2% vs. 2.8%) than the younger onset group. Cytomegalovirus infections were frequent in elderly onset patients (38.5% vs. 13.9%) but decreased with early glucocorticoid dose reduction and increased immunosuppressant and tocilizumab use. Elderly AOSD is not uncommon; these patients have different characteristics than younger-onset patients. Devising a way to control disease activity quickly while managing infections may be an important goal in elderly AOSD.Wastewater treatment plant effluents have been identified as a major contributor to increasing anthropogenic pollution in aquatic environments worldwide. Yet, little is known about the potentially adverse effects of wastewater treatment plant effluent on aquatic invertebrates. In this study, we assessed effects of wastewater effluent on the behaviour and metabolic profiles of damselfly larvae (Coenagrion hastulatum), a common aquatic invertebrate species. Four key behavioural traits activity, boldness, escape response, and foraging (traits all linked tightly to individual fitness) were studied in larvae before and after one week of exposure to a range of effluent dilutions (0, 50, 75, 100%). Effluent exposure reduced activity and foraging, but generated faster escape response. Metabolomic analyses via targeted and non-targeted mass spectrometry methods revealed that exposure caused significant changes to 14 individual compounds (4 amino acids, 3 carnitines, 3 lysolipids, 1 peptide, 2 sugar acids, 1 sugar). Taken together, these compound changes indicate an increase in protein metabolism and oxidative stress. Our findings illustrate that wastewater effluent can affect both behavioural and physiological traits of aquatic invertebrates, and as such might pose an even greater threat to aquatic ecosystems than previously assumed. More long-term studies are now needed evaluate if these changes are linked to adverse effects on fitness. The combination of behavioural and metabolomic assessments provide a promising tool for detecting effects of wastewater effluent, on multiple biological levels of organisation, in aquatic ecosystems.Understanding the dynamics of food trade, which involves a corresponding virtual trade in environmental resources, is relevant for its effects on the environment. Among the socioeconomic factors driving the international food market, trade agreements play a significant yet poorly understood role in facilitating access to worldwide trade. Focusing on the global trade of grain from 1993 to 2015, we investigate the role of trade agreements in activating new linkages and increasing traded volumes and their environmental implications. Through a data-driven approach, we show that the activation of a trade agreement among countries induces a more than six-fold increase in the probability of establishing a new link. Also, the presence of a trade agreement over time, not just its activation, relates to a more stable market since it reduces the probability of link deactivation by more than half. The trade links covered by agreements show larger flows and smoother inter-annual fluctuations. Furthermore, trade agreements encourage the development of more water-efficient flows by stimulating the exchange of crops with high water productivity values. The average economic water productivity of crops traded under trade agreements increases by 62% when considering total virtual water and even by 93% when focusing on blue water.
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